Respiratory distress syndrome (RDS) is the leading cause of death in prematurely born infants. It is estimated that over 25,000 deaths occur each year in the United States due to RDS. Neonatal RDS results from the inability of the lungs of premature infants to produce pulmonary surfactant. This surfactant is normally secreted by the type 2 alveoli cells of the lung and coats the alveolar lining. This coating acts to lower the surface tension at the air-liquid interface and greatly facilitates alveoli expansion upon inhalation thereby preventing collapse of air sacs on expiration. The lungs of infants lacking pulmonary surfactant are stiff, difficult to inflate, partially collapsed and fluid filled. Infants suffering from RDS become cyanotic and hypoxic.
While the precise composition of pulmonary surfactant is still uncertain, it is believed to be a complex of dipalmitoyl phosphatidylcholine (DPPC), a phospholipid, and apoprotein A (apo A), one of the two major protein components of the lung. The human apo A gene was recently isolated and its nucleotide sequence characterized by White et al., Nature, 317(26), 361 (1985). As a result, the amino acid sequence of apo A can, largely, be deduced.
Currently, neonatal RDS therapy is supportive in nature, directed toward assisting essential bodily functions and minimizing secondary complications until the newborn is able to breathe normally without assistance. In some severe cases, continuous positive airway pressure is effective by preventing lung collapse and by providing an oxygen enriched air supply. Although effective, such treatment presents risks of air leaks which can lead to interstitial pulmonary emphysema, pneumomediastinum and tension pneumothorax and can only be used where infant intensive care is available.
More recently, surfactant isolated by alveolar wash of sheep, Tween (fatty acid esters of polyethylene oxide sorbitan), and human surfactant have been shown to be effective when administered to human infants suffering from RDS and in animal failing lung models. The use of natural surfactant from animals and humans in the treatment of RDS, is however limited by the lack of its ready availability and the variability of the effectiveness of natural surfactant from batch to batch.
Applicant has discovered polypeptide-phospholipid complexes which consist of the amphipathic, helical portion of human apo A and certain of its analogs and a phospholipid such as DPPC. These complexes when administered to infants suffering from RDS act as a substitute for natural pulmonary surfactant.